JP2019524819A - Soft tissue hardening composition - Google Patents

Abstract

The present invention relates to a variety of compounds that can temporarily harden and harden soft tissue for soft tissue suture surgery. The compound according to the present invention can prevent sequelae due to the fact that the anastomosis is not performed properly by temporarily increasing the hardness or tensile force of the soft tissue to increase the suturing efficiency at the time of suturing the soft tissue. In addition, the compound according to the present invention can effectively prevent pancreatic leakage by temporarily increasing the hardness or tensile force of the pancreas among soft tissues to enhance the suture efficiency during pancreaticoduodenectomy. Can do. [Selection] Figure 3

Description

  The present invention relates to compounds that can temporarily harden and harden soft tissue for soft tissue suture surgery.

  The pancreas is an organ located in the back of the stomach that not only secretes various digestive enzymes to promote the breakdown of carbohydrates, proteins and fats that have passed through the stomach, but also insulin, glucagon It is an organ that produces important hormones. Absorption of nutrients is insufficient without sufficient secretion of digestive enzymes from the pancreas. Insulin and glucagon secretion also regulates vascular sugar concentrations. Research on the mechanisms that regulate the production and secretion of these various enzymes and hormones has become an important theme in relation to various diseases such as nutrition and diabetes and obesity.

  Major diseases that occur in connection with the pancreas include pancreatic cancer, pancreatitis, diabetes and the like. Diabetes mellitus is a disease that occurs when insulin secretion in the pancreas is decreased or resistance to the action of insulin occurs in other tissues. It is a dangerous disease to bring. In addition, pancreatic cancer is known as a disease with the highest mortality and poor prognosis among malignant tumors.

  The most common treatment methods for treating diseases related to the pancreas have been tried by administration of analgesics, antibiotics, anticancer agents, etc. and intravenous infusions. Pancreaticoduodenectomy has been performed to treat this.

  The pancreaticoduodenectomy was widely spread by Whipple et al. In 1912 after the first successful pancreatoduodenectomy was introduced by Kausch. Pancreaticoduodenectomy is an important surgical technique applied to the radical treatment of Vater's massive cancer around the pancreas head, common bile duct, and duodenal ulcer. This is a surgical method that is highly likely to occur. Until the 1970s, postoperative mortality was reported to be about 20%. Recently, mortality from pancreatoduodenectomy has been achieved due to the development of surgical techniques and anesthesia, patient management before and after surgery, and nutritional management. Is reported to be less than 5%.

  However, despite the rapid decrease in mortality, the frequency of postoperative complications has recently been reported to be 40-50%, especially pancreatic leakage, which is closely related to mortality. Is still reported to be 10-20%. When pancreatic leaks occur, they can cause intra-abdominal hemorrhages and abscesses, or septicemia, with associated mortality rates.

  According to various reports, it is known that the diameter of the pancreatic duct and the consistency of pancreatic parenchyma are involved as risk factors involved in the occurrence of pancreatic leakage. Here, in relation to the hardness of the pancreatic parenchyma, the pancreas remaining after pancreatectomy is very soft, and there is a high risk of the tissue becoming brittle at the time of suturing. The anastomosis is not performed properly even after the suturing, and pancreatic juice flows into the gap to cause the pancreatic leakage.

  Recently, pancreatic-jejunostomy or pancreato-gastrointestinal anastomosis, pancreatic duct-mucosal anastomosis or dunking method, stent insertion, etc. have been proposed to prevent the occurrence of pancreatic leakage after surgery. In addition to the surgical suturing method, somatostatin and fibrin glue are also proposed.

  The present inventors have found that a new compound synthesized with the structure of an existing antibiotic as a basic skeleton can temporarily cure the pancreas, and the efficiency of suturing during pancreatic surgery such as pancreatoduodenectomy as described above As a result, the present invention has been completed.

  In order to prevent the occurrence of pancreatic leakage after pancreaticoduodenectomy, the present inventors have developed a novel compound that can temporarily cure the pancreas so that pancreatic suture can be performed more efficiently, As a result, it was confirmed that the compound derivative according to the present invention can temporarily improve the strength and tensile force of soft tissues such as pancreas, and the present invention has been achieved.

  Accordingly, one object of the present invention is to provide a novel compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

  Another object of the present invention is to provide a method for producing the compound.

  Still another object of the present invention is to provide a pharmaceutical composition for soft tissue sclerosis.

  Still another object of the present invention is to provide a pharmaceutical composition for pancreatic sclerosis.

  Still another object of the present invention is to provide a pharmaceutical composition for preventing pancreatic leakage.

  Still another object of the present invention is to provide a method for selecting a soft tissue hardening substance.

  Hereinafter, various specific examples described in the present application will be described with reference to the drawings. In the following description, numerous specific details are set forth, such as specific forms, compositions, and processes, in order to provide a thorough understanding of the present invention. However, specific embodiments may be practiced without one or more of these specific details or with other known methods and forms. In other instances, well-known processes and manufacturing techniques have not been described as specific details in order not to unnecessarily obscure the present invention. Reference throughout this specification to “an embodiment” or “an embodiment” includes within the one or more embodiments of the invention the particular feature, form, composition or characteristic described in connection with the embodiment. Means that. Accordingly, the context of “in one embodiment” or “in an embodiment” expressed in various places throughout this specification is not necessarily indicative of the same embodiment of the invention. In addition, particular features, forms, compositions, or characteristics are combined in any suitable manner in one or more embodiments.

According to one embodiment of the present invention, a compound represented by the following Formula 1, a pharmaceutically acceptable salt or hydrate thereof is provided:
In Formula 1,
R is hydrogen or N (R ′) (R ″);
R ′ and R ″ are each independently hydrogen, a C _1-6 alkyl group or a C _1-6 alkenyl group;
R ₁ is hydrogen or a C _1-6 alkyl group;
The C _1-6 alkyl group of R ₁ is substituted or unsubstituted with R ₂ ;
R ₂ is selected from the group consisting of a C _1-6 alkenyl group, a C _3-7 cycloalkyl group, a cyano group, a C _1-6 alkyl group, a C _6-10 aryl group, —OR ₃ and —COOR ₄ ;
The aryl group of R ₂ is substituted or unsubstituted with halogen;
R ₃ is — (CH ₂ ) _m OR ₅ ;
m is an integer from 0 to 3;
R ₄ and R ₅ are each independently a C _1-6 alkyl group.

  In one embodiment of the present invention, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be preferably one or more selected from the compounds shown in Table 1 below.

As a preferred embodiment of the present invention, R ′ and R ″ may each independently be hydrogen or a C _1-6 alkenyl group.

As a preferred embodiment of the present invention, R ₁ may be hydrogen or a C _1-4 alkyl group.

As a preferred specific example of the present invention, R ₂ represents a C _1-3 alkenyl group, a C _5-7 cycloalkyl group, a cyano group, a C _1-3 alkyl group, a C _6-8 aryl group, —OR ₃ and —. It may be selected from the group consisting of COOR ₄ .

  In the present invention, the compound represented by Formula 1 is preferably (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1- Azabicyclo [3.2.0] heptane-2-carboxylic acid; allyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] Heptane-2-carboxylate; cyclohexylmethyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] Heptane-2-carboxylate; 3-cyanopropyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia 1-azabicyclo [3.2.0] heptane-2-carboxylate; and (2S, 5R, 6R) -6-((S) -2-amino-2-phenylacetamido) -3,3-dimethyl-7 It may be one or more selected from the group consisting of -oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid.

  The present invention also provides a pharmaceutically acceptable salt of the compound represented by Formula 1. Pharmaceutically acceptable salts are less toxic to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. The pharmaceutically acceptable salt may be an addition salt of the acid compound with a pharmaceutically acceptable free base, but is not limited thereto.

  Preferred salt forms of the compound according to the present invention include, for example, a salt having an inorganic acid, for example, hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphate, nitrate, and carbonate; and a salt having an organic acid, For example, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid and acetyl Salicylic acid (aspirin); or salts with amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, and proline; salts with sulfonic acids such as methane Sulfonate, ethanesulfur , Benzenesulfonate and toluenesulfonate; metal salts by reaction with an alkali metal, e.g., sodium and potassium; is a salt having an ammonium ion, but is not limited thereto.

  The salt can be produced by a usual method. For example, the compound of Formula 1 is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallized after adding a free acid or a free base. Can do.

  In the present invention, a preferable example of a pharmaceutically acceptable salt of the compound represented by Formula 1 may be one or more selected from the salts shown in Table 2 below.

  In addition, the hydrate form of the compound represented by Formula 1 is also included in the scope of the present invention.

  According to another embodiment of the present invention, there is provided a pharmaceutical composition for soft tissue sclerosis comprising as an active ingredient the compound represented by Chemical Formula 1, a pharmaceutically acceptable salt or hydrate thereof.

  In the present invention, the “soft tissue” may be one or more tissues selected from the group consisting of pancreas, liver, nerve, ligament, serosa, fascia, intervertebral disc, and blood vessel, and preferably May be the pancreas, but is not limited thereto.

  The compound represented by Formula 1 and the pharmaceutically acceptable salt and hydrate thereof provided in the present invention temporarily increase the hardness or tensile force of soft tissue and increase the suturing efficiency at the time of suturing the soft tissue. In this way, it is possible to prevent sequelae and the like due to an anastomosis not being performed properly.

  According to another embodiment of the present invention, there is provided a pharmaceutical composition for preventing pancreatic leakage comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

  The compound represented by Formula 1 and the pharmaceutically acceptable salt and hydrate thereof provided by the present invention temporarily increase the hardness or tensile force of pancreas, and can be sutured during pancreatoduodenectomy. By increasing the efficiency, pancreatic leakage can be effectively prevented.

  According to still another embodiment of the present invention, soft tissue is cured, comprising administering an effective amount of the compound represented by Formula 1 or a pharmaceutically acceptable salt or hydrate thereof to a subject. Regarding the method.

  In the present invention, the target object may be a target object that temporarily needs soft tissue hardening, and more preferably, a target object that requires a suturing operation for soft tissue.

  In the present invention, the compound represented by Chemical Formula 1, a pharmaceutically acceptable salt or hydrate thereof is administered to the soft tissue of the subject.

  In the present invention, the “soft tissue” may be one or more tissues selected from the group consisting of pancreas, liver, nerve, ligament, serosa, fascia, intervertebral disc, and blood vessel, and preferably May be the pancreas, but is not limited thereto.

  According to still another embodiment of the present invention, prevention of pancreatic leakage comprising the step of administering to a subject an effective amount of the compound represented by Formula 1 above, a pharmaceutically acceptable salt or hydrate thereof. Regarding the method.

  In the present invention, the subject may be a subject requiring pancreatoduodenectomy.

  In the present invention, the compound represented by Formula 1 or a pharmaceutically acceptable salt or hydrate thereof is administered to the pancreas of the subject.

  As used herein, an “effective amount” refers to an amount sufficient to achieve a temporary change in hardness or tensile force in the soft tissue or pancreas of a subject.

  According to still another embodiment of the present invention, soft tissue sclerosis comprising as an active ingredient a compound selected from the group consisting of hydroxyquinoline compounds, derivatives thereof, pharmaceutically acceptable salts and hydrates thereof. Pharmaceutical compositions are provided.

  In the present invention, the hydroxyquinoline compound and its derivative may be one or more selected from the compounds shown in Table 3 below.

  In the present invention, the derivative of the hydroxyquinoline compound is preferably 7-chloro-4-hydroxy-3-quinolinecarboxylic acid; 5-chloro-8-hydroxyquinoline; 5-chloro-8-hydroxy-7-iodoquinoline. 5,7-diiodo-8-hydroxyquinoline; 4,8-dihydroxyquinoline-2-carboxylic acid; 4-hydroxy-7-trifluoromethyl-3-quinolinecarboxylic acid; 3-hydroxyisoquinoline; 4-hydroxyquinoline; One or more selected from the group consisting of 6-hydroxyquinoline; 2-hydroxyquinoline; 8-hydroxyquinoline-7-carboxylic acid; and 8-hydroxyquinoline, more preferably 3-hydroxyisoquinoline It may be.

  The present invention also provides a pharmaceutically acceptable salt of the hydroxyquinoline compound or a derivative of the compound. Pharmaceutically acceptable salts are less toxic to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. The pharmaceutically acceptable salt may be a pharmaceutically acceptable free acid and an acid addition salt of the basic compound, but is not limited thereto.

  Preferred salt forms of the compounds according to the invention include, for example, salts with inorganic acids, such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphates, nitrates and carbonates; and salts with organic acids, such as , Formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid and acetylsalicylic acid (Aspirin); or salts with amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine and proline; salts with sulfonic acids such as methanesulfonate, Ethanesulfone Metal salt by reaction with an alkali metal, e.g., sodium and potassium; DOO, benzenesulfonate and toluenesulfonate is a salt having an ammonium ion, but is not limited thereto.

  The salt can be produced by a usual method. For example, the hydroxyquinoline compound or a derivative of the compound is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallized after adding a free acid or free base. Can be manufactured.

  In addition, a hydrate form of the hydroxyquinoline compound or a derivative of the compound is also included in the scope of the present invention, and may preferably be a hydrate shown in Table 4 below, but is not limited thereto. I don't mean.

  In the present invention, the “soft tissue” may be one or more tissues selected from the group consisting of pancreas, liver, nerve, ligament, serosa, fascia, intervertebral disc, and blood vessel, and preferably May be the pancreas, but is not limited thereto.

  The hydroxyquinoline compound, derivative thereof, pharmaceutically acceptable salt, and hydrate of the present invention can temporarily increase the hardness or tensile force of soft tissue to increase the suturing efficiency at the time of suturing soft tissue. It is possible to prevent sequelae due to the anastomosis not being performed properly.

  According to still another embodiment of the present invention, a pharmaceutical composition for preventing pancreatic leakage comprising, as an active ingredient, a compound selected from the group consisting of hydroxyquinoline compounds, derivatives thereof, pharmaceutically acceptable salts and hydrates thereof. A composition is provided.

  In the present invention, the hydroxyquinoline compound and its derivative may be one or more selected from the compounds shown in Table 3.

  In the present invention, the derivative of the hydroxyquinoline compound is preferably 5-hydroxyquinoline; 7-chloro-4-hydroxy-3-quinolinecarboxylic acid; 5-chloro-8-hydroxyquinoline; 5-chloro-8-hydroxy. -7-iodoquinoline; 5,7-diiodo-8-hydroxyquinoline; 4,8-dihydroxyquinoline-2-carboxylic acid; 4-hydroxy-7-trifluoromethyl-3-quinolinecarboxylic acid; 3-hydroxyisoquinoline; It may be one or more selected from the group consisting of 4-hydroxyquinoline; 6-hydroxyquinoline; 2-hydroxyquinoline; 8-hydroxyquinoline-7-carboxylic acid; and 8-hydroxyquinoline, and more preferably 3-hydroxyisoquinoline may also be used.

  The present invention also provides a pharmaceutically acceptable salt of the hydroxyquinoline compound or a derivative of the compound. Pharmaceutically acceptable salts are less toxic to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. The pharmaceutically acceptable salt may be a pharmaceutically acceptable free acid and an acid addition salt of the basic compound, but is not limited thereto.

  Preferred salt forms of the compounds according to the invention include, for example, salts with inorganic acids, such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphates, nitrates and carbonates; and salts with organic acids, such as , Formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid and acetylsalicylic acid (Aspirin); or salts with amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine and proline; salts with sulfonic acids such as methanesulfonate, Ethanesulfone Metal salt by reaction with an alkali metal, e.g., sodium and potassium; DOO, benzenesulfonate and toluenesulfonate is a salt having an ammonium ion, but is not limited thereto.

  The salt can be produced by a usual method. For example, the hydroxyquinoline compound or a derivative of the compound is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, 1,4-dioxane, and then crystallized after adding a free acid or free base. Can be manufactured.

  In addition, a hydrate form of the hydroxyquinoline compound or a derivative thereof is also included in the scope of the present invention, and may preferably be a hydrate shown in Table 4, but is not limited thereto. Do not mean.

  The hydroxyquinoline compounds, derivatives thereof, pharmaceutically acceptable salts and hydrates thereof of the present invention temporarily increase the hardness or tensile force of the pancreas to enhance the suture efficiency during pancreaticoduodenectomy Thus, pancreatic leakage can be effectively prevented.

  According to yet another embodiment of the present invention, the step of administering to a subject an effective amount of a compound selected from the group consisting of a hydroxyquinoline compound, a derivative thereof, a pharmaceutically acceptable salt and a hydrate thereof. And a method of hardening a soft tissue.

  In the present invention, the hydroxyquinoline compound, derivatives thereof, pharmaceutically acceptable salts and hydrates thereof overlap with those described in the pharmaceutical composition for soft tissue sclerosis according to the present invention. Omitted.

  In the present invention, the target object may be a target object that temporarily needs soft tissue hardening, and more preferably, a target object that requires a suturing operation for soft tissue.

  In the present invention, the hydroxyquinoline compound, derivative thereof, pharmaceutically acceptable salt or hydrate thereof is administered to the soft tissue of the subject.

  In the present invention, the “soft tissue” may be one or more tissues selected from the group consisting of pancreas, liver, nerve, ligament, serosa, fascia, intervertebral disc, and blood vessel, and preferably May be the pancreas, but is not limited thereto.

  According to yet another embodiment of the present invention, the step of administering to a subject an effective amount of a compound selected from the group consisting of a hydroxyquinoline compound, a derivative thereof, a pharmaceutically acceptable salt and a hydrate thereof. The present invention relates to a method for preventing pancreatic leakage.

  In the present invention, the hydroxyquinoline compound, derivative thereof, pharmaceutically acceptable salt and hydrate thereof overlap with those described in the pharmaceutical composition for preventing pancreatic leakage according to the present invention, and are described in detail below. Is omitted.

  In the present invention, the subject may be a subject requiring pancreatoduodenectomy.

  In the present invention, the hydroxyquinoline compound, derivative thereof, pharmaceutically acceptable salt or hydrate thereof is administered to the pancreas of the subject.

According to still another embodiment of the present invention, a soft tissue sclerosis comprising as an active ingredient a compound represented by any one of the following chemical formulas 2 to 9, a pharmaceutically acceptable salt or hydrate thereof: Providing a pharmaceutical composition for:

  In the present invention, specific names of the compounds represented by Chemical Formulas 2 to 9 are as shown in Table 5 below.

  The present invention also provides pharmaceutically acceptable salts of the compounds represented by Formulas 2-9. Pharmaceutically acceptable salts are less toxic to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. The pharmaceutically acceptable salt may be, but is not limited to, an addition salt of a pharmaceutically acceptable base and an acid compound of Formulas 2-9.

  Preferred salt forms of the compounds according to the invention include, for example, salts with inorganic acids, such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphates, nitrates and carbonates; and salts with organic acids, such as , Formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid and acetylsalicylic acid (Aspirin); or salts with amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine and proline; salts with sulfonic acids such as methanesulfonate, Ethanesulfone Metal salts by reaction with an alkali metal, e.g., sodium and potassium; DOO, benzenesulfonate and toluenesulfonate is a salt having an ammonium ion, but is not limited to these.

  The salt can be produced by a usual method. For example, the compound represented by any one of the chemical formulas 2 to 9 is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, and then free acid or free It can be produced by crystallization after adding a base.

  In the present invention, preferred examples of the pharmaceutically acceptable salt of the compound represented by Formula 8 may be salts shown in Table 6 below.

  In addition, hydrate forms of the compounds represented by Formulas 2 to 9 are also included in the scope of the present invention.

  In the present invention, the “soft tissue” may be one or more tissues selected from the group consisting of pancreas, liver, nerve, ligament, serosa, fascia, intervertebral disc, and blood vessel, and preferably May be the pancreas, but is not limited thereto.

  The compounds represented by the chemical formulas 2 to 9, and pharmaceutically acceptable salts and hydrates thereof according to the present invention temporarily increase the soft tissue hardness or tensile force to increase the suturing efficiency at the time of suturing the soft tissue. In this way, it is possible to prevent sequelae and the like due to an anastomosis not being performed properly.

According to still another embodiment of the present invention, pancreatic leakage comprising a compound represented by any one of the following chemical formulas 2 to 9, a pharmaceutically acceptable salt or hydrate thereof as an active ingredient: Prophylactic pharmaceutical compositions are provided:

  The present invention also provides pharmaceutically acceptable salts of the compounds represented by Formulas 2-9. Pharmaceutically acceptable salts are less toxic to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. Examples of the pharmaceutically acceptable salt include, but are not limited to, an addition salt of a pharmaceutically acceptable free base and the acid compound represented by Formulas 2-9.

  Preferred salt forms of the compounds according to the invention include, for example, salts with inorganic acids, such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphates, nitrates and carbonates; and salts with organic acids, such as , Formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, trifluoroacetic acid and acetylsalicylic acid (Aspirin); or salts with amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine and proline; salts with sulfonic acids such as methanesulfonate, Ethanesulfone Metal salt by reaction with an alkali metal, e.g., sodium and potassium; DOO, benzenesulfonate and toluenesulfonate is a salt having an ammonium ion, but is not limited thereto.

  The salt can be produced by a usual method. For example, the compound represented by any one of the chemical formulas 2 to 9 is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, and then free acid or free It can be produced by crystallization after adding a base.

  In the present invention, preferred examples of the pharmaceutically acceptable salt of the compound represented by Formula 8 may be the salts shown in Table 6.

  In addition, hydrate forms of the compounds represented by Formulas 2 to 9 are also included in the scope of the present invention.

The compound represented by the chemical formulas 2 to 9, the pharmaceutically acceptable salt or hydrate thereof according to the present invention can be used for suturing during pancreaticoduodenectomy by temporarily increasing the hardness or tensile force of the pancreas. By increasing the efficiency, pancreatic leakage can be effectively prevented.

  According to still another embodiment of the present invention, an effective amount of a compound represented by any one of Formulas 2 to 9, a pharmaceutically acceptable salt or hydrate thereof is administered to a subject. And a method of hardening the soft tissue.

  In the present invention, the compounds represented by the chemical formulas 2 to 9, pharmaceutically acceptable salts and hydrates thereof overlap with those described in the pharmaceutical composition for soft tissue sclerosis according to the present invention. The description is omitted.

  In the present invention, the target object may be a target object that temporarily needs soft tissue hardening, and more preferably, a target object that requires a suturing operation for soft tissue.

  In the present invention, the compound represented by any one of Chemical Formulas 2 to 9, its pharmaceutically acceptable salt or hydrate is administered to the soft tissue of the subject.

  In the present invention, the “soft tissue” may be one or more tissues selected from the group consisting of pancreas, liver, nerve, ligament, serosa, fascia, intervertebral disc, and blood vessel, and preferably May be the pancreas, but is not limited thereto.

  According to still another embodiment of the present invention, an effective amount of a compound represented by any one of Formulas 2 to 9, a pharmaceutically acceptable salt or hydrate thereof is administered to a subject. And a method of preventing pancreatic leakage.

  In the present invention, the compounds represented by the chemical formulas 2 to 9, and pharmaceutically acceptable salts or hydrates thereof overlap with those described in the pharmaceutical composition for preventing pancreatic leakage according to the present invention. Detailed description is omitted.

  In the present invention, the subject may be a subject requiring pancreatoduodenectomy.

  In the present invention, the compound represented by the chemical formulas 2 to 9, its pharmaceutically acceptable salt or hydrate is administered to the pancreas of the subject.

According to still another embodiment of the present invention, a compound represented by the following chemical formula 10 and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) (18-crown-6) Dissolving (1,4,7,10,13,16-hexaoxycyclooctadecane) in an organic solvent;
And adding a compound represented by the following Formula 11 to the dissolved solution and stirring to synthesize the compound:
[Chemical formula 11]
R ₆ -Br
In Formula 10,
R is hydrogen or N (R ′) (R ″);
R ′ and R ″ are each independently hydrogen, a C _1-6 alkyl group or a C _1-6 alkenyl group,
In Formula 11,
R ₆ is hydrogen or a C _1-6 alkyl group;
The C _1-6 alkyl group of R ₆ is substituted or unsubstituted with R ₇ ;
R ₇ is selected from the group consisting of a C _1-6 alkenyl group, a C _3-7 cycloalkyl group, a cyano group, a C _1-6 alkyl group, a C _6-10 aryl group, —OR ₈ and —COOR ₉ ;
The aryl group of R ₇ is substituted or unsubstituted with halogen;
R ₈ is — (CH ₂ ) _n OR ₁₀ ;
n is an integer from 0 to 3;
R ₉ and R ₁₀ are each independently C _1-6 alkyl.

  In the present invention, the compound represented by Chemical Formula 11 includes 3-bromopropene, (bromomethyl) cyclohexane, 4-bromobutyronitrile, tert-butyl. Bromopropionate, 1-bromo-2-methylpropane, 2-fluorobenzyl bromide and 2- (2-ethoxyethoxy) ethyl bromide (2- (2-ethyoxy) ethyl bromide) may be selected from the group consisting of There is no limitation as long as substitutable alkyl bromide reacts with Rubokishireto.

  In the present invention, the organic solvent is used for dissolving the compound, and is preferably an aprotic polar solvent. Specifically, dioxane, tetrahydrofuran (THF), acetone, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), 1-methyl-2-pyrrolidone (NMP) and the like can be used, and dimethylformamide (DMF) can be used. Most preferably it is used.

  According to yet another embodiment of the present invention, (a) measuring the hardness or tensile force of the pancreas of a mammal excluding a human not treated with the compound; and (b) a mammal excluding a human treated with the candidate compound. Measuring the pancreas hardness or tensile force of the pancreas, and (c) the pancreas hardness or tensile force measured in the step (b) is higher than the pancreas hardness or tensile force measured in the step (a) A method for selecting a substance for pancreatic sclerosis comprising the step of determining the compound as a substance for pancreatic sclerosis.

In the present invention, the KRM-60027 (penicillin G potassium salt) and the KRM-60036 (ampicillin sodium salt) compound are (R) -4-thia-1-azabicyclo [3,2,0] hepta-7- It is an antibiotic having ON as a skeleton and is the same series of antibiotics. The difference between the two compounds is that KRM-60027 is a potassium salt and KRM-60036 is a sodium salt. KRM-60027 has a CH ₂ -bond at the benzyl position on the left side of the skeleton, whereas KRM-60036 is, CH ₂ benzyl position - has the effect of increasing by replacing one hydrogen atom present in the binding to the amino group of the drug pharmacokinetic (pharmacokinetics, PK). KRM-60027 showed the result that the pancreas increased the tensile force to a significant level, and in the case of KRM-60036, it was found that the strength of the pancreas was significantly increased.

  In the present invention, KRM-60037 (D-penicillamine) is a drug having a simple structure and has a molecular weight of only 149, but showed an effect of increasing the tensile force by 1.5 times. In particular, since such a small molecule has many chemically deformable portions, it has an advantage that the tensile force and hardness of the pancreas can be sufficiently increased by attaching various substituents.

  In the present invention, KRM-60042 (8-hydroxyquinoline) is also easy to attach various substituents to a simple skeleton with a low molecular weight substance of 145. In the case of KRM-60042, it can be confirmed that the hardness and tensile force of the pancreas are all significantly increased.

  In the present invention, KRM-60049 (ketoconazole) has an advantage that it has a molecular weight of 530, has an ideal value, has many functional groups capable of forming salts such as piperazine and imidazole, and can produce various salts. is there.

  In the present invention, “hardness” means the magnitude of resistance to deformation of the pancreas when an external force is applied to a soft tissue, preferably the outside of the pancreas, among human organs. The hardness according to the present invention is measured using a hardness meter, and the hardness of the pancreas is determined by using the elastic modulus (EM), the Hooke's law and the Hertz contact stress theory (Hertz). This is done by measuring based on the contract stress theory. The EM measures the stiffness of a resilient material, and is determined by the “Hokes's law” as “stresses present by an axis” and “within the range of stresses”. It is expressed as a ratio of the “total strain” existing in the axis of

  In the present invention, “tensile force” means a force generated in a soft tissue, preferably in the pancreas, in human organs. When an external force acts by stretching or pulling, it resists it. It means the tolerance that occurs in the organ. The measurement of the tensile force according to the present invention is measured using a dynamometer, and more specifically, the tensile force is calculated by measuring a suture-holding capacity using a Newton dynamometer. . At this time, the tensile force is calculated by adding the weight of the tissue.

In one embodiment of the present invention, “alkyl” means a saturated linear or branched hydrocarbon group such as methyl, ethyl, propyl, butyl, isobutyl, tertiary butyl and pentyl. As used herein, “C _1-6 alkyl group” means an alkyl group having 1 to 6 carbon atoms.

  In one embodiment of the invention “cycloalkyl” means a monocyclic or polycyclic saturated ring containing carbon and hydrogen atoms.

  In one embodiment of the present invention, “aryl” means a wholly or partially unsaturated monocyclic or polycyclic carbocycle having aromatic character. The aryl group of the present invention is preferably monoaryl or biaryl.

  In one embodiment of the present invention, “alkenyl” refers to an alkyl residue having one or more carbon-carbon double bonds. Here, alkyl is as defined above.

  In one embodiment of the present invention, “halogen” or “halo” means fluoro, chlorine, bromine or iodine unless otherwise stated.

  The pharmaceutical composition of the present invention includes not only the active ingredient compound but also a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention is usually used for drug formulation, and is lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, potassium phosphate. , Alginate, gelatin, potassium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil It is not something.

  The pharmaceutical composition according to the invention may additionally contain lubricants, wetting agents, sweetening agents, flavoring agents, emulsifying agents, suspending agents, and preservatives. For details of suitable pharmaceutically acceptable carriers and dosage forms, reference can be made to Remington's Pharmaceutical Sciences (19th edition, 1995).

  The pharmaceutical composition according to the present invention can be administered orally or parenterally. Specifically, it may be administered parenterally. For parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or intraarticular injection may be used. More specifically, it is administered by intramuscular injection or intraperitoneal injection.

  The preferred dosage of the pharmaceutical composition of the present invention is the method of drug formulation, method of administration, patient age, weight, sex, pathological condition, food, administration time, route of administration, excretion rate and the pharmaceutical composition used. It varies according to the sensitivity to. Preferably, the pharmaceutical composition of the present invention is administered at a daily dose of 0.001 to 10,000 mg / kg (body weight).

  According to the prior art known to those skilled in the art, the pharmaceutical composition according to the present invention is finally formulated into a pharmaceutically acceptable carrier and / or excipient as described above. It is offered in various forms including unit volume form and multi-volume form. Non-limiting examples of dosage forms include, but are not limited to, emulsions or aqueous media in solutions, suspensions or oils, elixirs, powders, granules, tablets and capsules. In addition, a dispersant or stabilizer may be additionally contained.

  The compound according to the present invention can prevent sequelae and the like due to the fact that the anastomosis is not properly performed by temporarily increasing the hardness or tensile force of the soft tissue to increase the suturing efficiency at the time of suturing the soft tissue.

  In addition, the compound according to the present invention can effectively prevent pancreatic leakage by temporarily increasing the hardness or tensile force of the pancreas among soft tissues, thereby increasing the suturing efficiency during pancreatoduodenectomy. Can do.

In one embodiment of the present invention, after treatment of mouse pancreas with the antibiotics KRM-60027, KRM-60036, KRM-60037, KRM-60042 and KRM-60049 of the present invention, changes in the hardness of the pancreas are graphically represented. It is shown. In one embodiment of the present invention, the mouse pancreas is treated with the antibiotics KRM-60027, KRM-60036, KRM-60037, KRM-60042 and KRM-60049 of the present invention, and then the change in the tensile force of the pancreas is graphed. It is shown by. In one Example of this invention, after processing KRM-60028, KRM-60029, and KRM-60030 which concerns on this invention to the pancreas of a mouse | mouth, a change of the hardness of a pancreas is shown with a graph. In one Example of this invention, after processing KRM-60028, KRM-60029, and KRM-60030 which concerns on this invention to the pancreas of a mouse | mouth, a change of the tensile force of a pancreas is shown with a graph. In one Example of this invention, after processing KRP-00001-KRP-00017 which concerns on this invention to the pancreas of a mouse | mouth, a change of the hardness of a pancreas is shown with a graph. In one Example of this invention, after processing KRP-00001-KRP-00017 which concerns on this invention to the pancreas of a mouse | mouth, the change of the tensile force of a pancreas is shown with a graph. In one Example of this invention, after processing the KRM-60077-KRM-60088 which concerns on this invention to the pancreas of a mouse | mouth, a change of the hardness of a pancreas is shown with a graph. In one Example of this invention, after processing KRM-60077-KRM-60088 which concerns on this invention to the pancreas of a mouse | mouth, a change of the tensile force of a pancreas is shown with a graph.

According to one embodiment of the present invention, a compound represented by the following Formula 1, a pharmaceutically acceptable salt or hydrate thereof is provided:
In Formula 1,
R is hydrogen or N (R ′) (R ″);
R ′ and R ″ are each independently hydrogen, a C _1-6 alkyl group or a C _1-6 alkenyl group;
R ₁ is hydrogen or a C _1-6 alkyl group;
The C _1-6 alkyl group of R ₁ is substituted or unsubstituted with R ₂ ;
R ₂ is selected from the group consisting of a C _1-6 alkenyl group, a C _3-7 cycloalkyl group, a cyano group, a C _1-6 alkyl group, a C _6-10 aryl group, —OR ₃ and —COOR ₄ ;
The aryl group of R ₂ is substituted or unsubstituted with halogen;
R ₃ is — (CH ₂ ) _m OR ₅ ;
m is an integer from 0 to 3;
R ₄ and R ₅ are each independently a C _1-6 alkyl group.

  According to another embodiment of the present invention, there is provided a pharmaceutical composition for soft tissue sclerosis comprising as an active ingredient the compound represented by Chemical Formula 1, a pharmaceutically acceptable salt or hydrate thereof.

  According to still another embodiment of the present invention, soft tissue sclerosis comprising as an active ingredient a compound selected from the group consisting of hydroxyquinoline compounds, derivatives thereof, pharmaceutically acceptable salts and hydrates thereof. Pharmaceutical compositions are provided.

According to still another embodiment of the present invention, a soft tissue sclerosis comprising as an active ingredient a compound represented by any one of the following chemical formulas 2 to 9, a pharmaceutically acceptable salt or hydrate thereof: Providing a pharmaceutical composition for:

  Hereinafter, the present invention will be described in more detail through examples. These examples are merely to illustrate the present invention more specifically, and it is understood by those skilled in the art that the scope of the present invention is not limited by these examples by the gist of the present invention. It will be self-evident.

<Example 1: Selection of basic compound for synthesis of compound for pancreatic sclerosis>
In order to select a basic compound for synthesizing a compound capable of enhancing the function of pancreas, a total of 23 antibiotics shown below were prepared:

  More specifically, 3 mice were treated with each of the antibiotics shown above at a concentration of 1 mM, and as a control group, 3 mice were treated with phosphate buffered saline (PBS). . Then, comparing the tension and hardness of the pancreas of the control group mice not treated with antibiotics and the mice treated with antibiotics, select the antibiotics whose tensile force and hardness increased during treatment Thus, basic compounds were selected.

  As a result, of the 23 types of compounds, only the KRM-60027, KRM-60036, KRM-60037, KRM-60042 and KRM-60049 compounds confirmed the effect of increasing the tensile strength and hardness of the pancreas, and compared with the control group. The changes in pancreas hardness and tensile force after treatment with these five compounds are shown graphically in FIGS. However, hardness and tensile force were measured using the following methods.

(1) Measurement of hardness In order to measure the resistance of the pancreas using a hardness meter, the elastic modulus of the resected pancreas (EM) is calculated using the Hooke's law and Hertz's law. Based on the contact stress theory, the resistance of the pancreas was calculated by the following formula using Venustron (Axiom, Koriyama, Japan).
(F, force; v, Poisson's ratio; t, variant of compression; r, diameter of a rigid spherical probe that pushes the object vertically)

(2) Measurement of tensile force The tensile force of the pancreas was measured using a dynamometer. After the pancreas piece was prepared at 1 × 1 × 1.5 cm, a silk 4-0 suture was passed through the tissue to form a knot, and the suture holding capacity was measured using a Newton dynamometer. did. At this time, the tensile force was calculated by adding the weight of the tissue.

  As shown in FIGS. 1 and 2, KRM-60027 (Penicillin G potassium salt; Penicillin G potassium salt), KRM-60036 (ampicillin sodium salt), KRM-60037 according to the present invention is applied to mouse pancreas. Treatment of five antibiotics (D-penicillamine; KRM-60042 (hydroxyquinoline; 8-hydroxyquinoline) and KRM-60049 (ketoconazole; Ketoconazole)) controls pancreatic tension and / or hardness. It was confirmed that it increased markedly compared with the group. More specifically, it was confirmed that KRM-60027 increased the tensile force of the pancreas to a significant level, and in the case of KRM-60036, it significantly increased the strength of the pancreas. KRM-60037 is a drug with a simple structure and has a molecular weight of only 149. However, KRM-60042 and KRM-60049 have the effect of increasing the tensile force of the pancreas by 1.5 times. It was confirmed that all the tensile forces were increased to a high level.

  Based on these results, five types of antibiotics were selected as basic compounds that can cure the pancreas.

Synthesis Example 1 Synthesis of derivatives of KRM-60027 In Example 1, various alkyl bromides at the carboxylate position of KRM-60027 were started using the KRM-60027 compound which showed an excellent effect in increasing the tensile force of pancreas. The compounds were combined to synthesize the final pancreatic function enhancing compound.

Synthesis Example 1-1: Synthesis of KRM-60028
The KRM-60027 compound and 18-crown-6 (1,4,7,10,13,16-Hexaoxycyclotadecane) used as starting materials were dissolved in DMF (dimethylformamide) and then 3-bromopropene (alkyl bromide). 3-bromopropene) was added and stirred at room temperature for 24 hours. After confirming the completion of the reaction by thin layer chromatography (Thin-Layer Chromatography, TLC), ethyl acetate was added and washed several times with water. After separating the ethyl acetate layer containing the product separately, anhydrous sodium sulfate was added to remove the remaining water and concentrated. And it refine | purified using column chromatography (Column chromatography), The final product KRM-60028 by which the carboxylate of KRM-60027 was substituted by the allyl was obtained.

Synthesis Example 1-2: Synthesis of KRM-60029
In the same manner as described in Preparation 1-1 except that (bromomethyl) cyclohexane is used instead of 3-bromopropene as the alkyl bromide, the carboxylate of KRM-60027 is finally substituted with cyclohexyl. The product was obtained.

Synthesis Example 1-3: Synthesis of KRM-60030
Except for using 4-bromobutyronitrile instead of 3-bromopropene as the alkyl bromide, the carboxylate of KRM-60027 was replaced with cyanobutyl in the same manner as described in Preparation 1-1. The final product was obtained.

Synthesis Example 1-4: Synthesis of KRM-60077
The carboxylate of KRM-60027 is tert-butyl in the same manner as described in Preparation 1-1 except that tert-butyl bromopropionate is used as the alkyl bromide instead of 3-bromopropene. The final product substituted with propionate was obtained.

Synthesis Example 1-5: Synthesis of KRM-60078
Except for using 1-bromo-2-methylpropane instead of 3-bromopropene as the alkyl bromide, the carboxylate of KRM-60027 is converted to isobutyl in the same manner as described in Preparation 1-1. A substituted final product was obtained.

Synthesis Example 1-6: Synthesis of KRM-60079
Except for using 2-fluorobenzyl bromide instead of 3-bromopropene as the alkyl bromide, the carboxylate of KRM-60027 is converted to 2-fluorobenzyl in the same manner as described in Preparation 1-1. A substituted final product was obtained.

Synthesis Example 1-7: Synthesis of KRM-60080
Except for using 2- (2-ethoxyethoxy) ethyl bromide instead of 3-bromopropene as the alkyl bromide, the carboxylate of KRM-60027 is prepared in the same manner as described in Preparation Example 1-1. The final product substituted with ethylene glycol was obtained.

Example 2: Additional selection of compound for pancreatic sclerosis After KRM-60028, KRM-60029 and KRM-60030 synthesized in Synthesis Example 1 were treated on mouse pancreas in the same manner as in Example 1, after which Changes in the pancreas hardness and tensile force were measured in comparison with the untreated control group, and the results are shown graphically in FIGS.

  As shown in FIGS. 3 and 4, treatment of mouse pancreas with KRM-60028, KRM-60029, and KRM-60030 of the present invention resulted in an increase in all of the control group, pancreatic hardness and tensile force. I was able to confirm. Referring to Example 1, in the case of KRM-60027, which is the initial compound, the change in the hardness of the pancreas was slight compared to the control group, and the tensile force was significantly increased, but KRM, which is a compound deformed from this, was used. In the case of -60028, KRM-60029, and KRM-60030, it was confirmed that the hardness or tensile force of the pancreas was all increased. In particular, a KRM-60030 compound having a functional group that can serve as a hydrogen bonding acceptor by having a nitrile group at the right end as a derivative of a KRM-60027 carboxylate group with a cyanopropyl group. In this case, it was confirmed that the hardness of the pancreas increased 1.5 times and the tensile force also increased 2 times compared with the control group.

  Accordingly, it can be seen that the compound represented by Chemical Formula 1 of the present invention increases the hardness and tensile force of the pancreas and temporarily hardens the pancreas.

Synthesis Example 2 Synthesis of Derivative of KRM-60036 In Example 1, the carboxylate was retained while retaining the amine of KRM-60036, starting from the KRM-60036 compound that showed an excellent effect in increasing pancreatic hardness. An alkyl bromide compound was selectively introduced only at the position to synthesize a compound for enhancing pancreatic function. Specifically, after the BRM protection of the amine of the KRM-60036 compound used as a starting material as shown in the following reaction formula 1, 3-bromopropene, (bromomethyl) as an alkyl bromide as shown in the reaction formula 2. ) Using cyclohexane and 4-bromobutyronitrile, an alkyl group was introduced in the same manner as described in Preparation Example 1-1, followed by boc deprotection to obtain the final amine compound. .

Example 3: Derivative of KRM-60042 In Example 1, the KRM-60042 compound (Sigma-Aldrich, cat. No. 252565 148-24-3) which showed all excellent effects in increasing pancreatic hardness and tensile force. The following derivative compounds based on hydroxyl groups and quinolines as basic skeletons were prepared.

  A total of 17 compounds of KRP-0001 to KRP-00017 were treated on the mouse pancreas in the same manner as in Example 1, and then the changes in the pancreas hardness and tensile force were measured as compared with the control group without any treatment. The results are shown graphically in FIGS.

  As shown in FIGS. 5 and 6, among 17 types of derivatives of KRM-60042 having a quinoline as a skeleton, KRP-00001, KRP-00002, KRP-00003, KRP-00004, KRP-00005, KRP-00006, When eleven compounds, KRP-00009, KRP-00012, KRP-00013, KRP-00014 and KRP-00001, were treated, all of the hardness and tensile strength of the pancreas increased, in particular KRP-00001, KRP-00002, Tensile force increases 1.5 times or more when 10 kinds of KRP-00003, KRP-00004, KRP-00005, KRP-00009, KRP-00012, KRP-00013, KRP-00014 and KRP-00001 are treated. KRP-000 If you process the 0, compared with the control group, the tensile force is able to confirm that the increased 2.4-fold position.

  Thus, the hydroxyquinoline derivative according to the present invention proved the effect of significantly increasing the tensile force of the pancreas and confirmed that the hardness was also increased.

Example 4: Other compounds The compounds of KRM-60077 to KRM-60080 synthesized in Synthesis Example 1 and the compounds of KRM-6801 to KRM-60088 shown together below were prepared in the same manner as in Example 1 with the pancreas of the mouse. After treatment, changes in the pancreas hardness and tensile force were measured in comparison with the control group without any treatment, and the results are shown in graphs in FIGS.

  As shown in FIGS. 7 and 8, treatment with KRM-60077 to KRM-60088 compound increased the contrast, pancreatic hardness and / or tensile strength of the control group, and in particular, KRM-60077, KRM-60078, KRM It was confirmed that when the compounds of −60080, KRM-60081, KRM-60082 and KRM-60088 were treated, the hardness and tensile force of the pancreas were all increased to a significant level.

  Thereby, the said compound which concerns on this invention proved the effect which increases the tensile force of a pancreas significantly, and has confirmed that it also increased hardness.

  Based on the above experimental results, in the present invention, when various deformable compounds (derivatives) are synthesized based on the structure of an antibiotic that increases the tensile force and / or hardness of the pancreas, the compounds that effectively increase the function of the pancreas are selected. I was able to confirm that I could do it. In addition, when the compound of the present invention thus selected is processed into the pancreas, the hardness and tensile force of the pancreas are temporarily increased to enhance the suture efficiency of the pancreas in operations such as pancreaticoduodenectomy, As a result, it was found that pancreatic leakage could be prevented.

  The present invention relates to compounds that can temporarily harden and harden soft tissue for soft tissue suture surgery.

Claims (21)

A compound represented by the following chemical formula 1, a pharmaceutically acceptable salt or hydrate thereof:
In Formula 1,
R is hydrogen or N (R ′) (R ″);
R ′ and R ″ are each independently hydrogen, a C _1-6 alkyl group or a C _1-6 alkenyl group;
R ₁ is hydrogen or a C _1-6 alkyl group;
The C _1-6 alkyl group of R ₁ is substituted or unsubstituted with R ₂ ;
R ₂ is selected from the group consisting of a C _1-6 alkenyl group, a C _3-7 cycloalkyl group, a cyano group, a C _1-6 alkyl group, a C _6-10 aryl group, —OR ₃ and —COOR ₄ ;
The aryl group of R ₂ is substituted or unsubstituted with halogen;
R ₃ is — (CH ₂ ) _m OR ₅ ;
m is an integer from 0 to 3;
R ₄ and R ₅ are each independently C _1-6 alkyl. The compound according to claim 1, wherein the compound is one or more selected from the group consisting of the following compounds:
1) (2S, 5R, 6R) -3,3-Dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid ( (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid);
2) Allyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate (Allyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate);
3) Cyclohexylmethyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxy Rate (cyclohexylmethyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate);
4) 3-Cyanopropyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2 -Carboxylate (3-cyanopropyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2 -Carboxylate);
5) 3- (tert-Butoxy) -3-oxopropyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3 .2.0] Heptane-2-carboxylate (3- (tert-butoxy) -3-oxopropyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4 -Thia-1-azabicyclo [3.2.0] heptane-2-carboxylate);
6) Isobutyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate (Isobutyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate);
7) 2-Fluorobenzyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2 -Carboxylate (2-fluorobenzoyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2 -Carboxylate);
8) 2- (2-Ethoxyethoxy) ethyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2. 0] heptane-2-carboxylate (2- (2-ethoxyxy) ethyl (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo) [3.2.0] heptane-2-carboxylate);
9) (2S, 5R, 6R) -6-((R) -2-amino-2-phenylacetamide) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0 ] Heptane-2-carboxylic acid ((2S, 5R, 6R) -6-((R) -2-amino-2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [ 3.2.0] heptane-2-carboxylic acid);
10) (2S, 5R, 6R) -cyclohexylmethyl 6-((R) -2-amino-2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2 .0] Heptane-2-carboxylate ((2S, 5R, 6R) -cyclohexylmethyl6-((R) -2-amino-2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1- azabicclo [3.2.0] heptane-2-carboxylate);
11) (2S, 5R, 6R) -3-cyanopropyl 6-((R) -2-amino-2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3 .2.0] Heptane-2-carboxylate ((2S, 5R, 6R) -3-cyanopropyl6-((R) -2-amino-2-phenylacetamido) -3,3-dimethyl-7-oxo-4- thia-1-azabicyclo [3.2.0] heptane-2-carboxylate);
12) (2S, 5R, 6R) -allyl 6-((R) -2-amino-2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2. 0] heptane-2-carboxylate ((2S, 5R, 6R) -allyl6-((R) -2-amino-2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate);
13) (2S, 5R, 6R) -allyl 6-((R) -2- (allylamino) -2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3. 2.0] Heptane-2-carboxylate ((2S, 5R, 6R) -allyl6-((R) -2- (allylamino) -2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia -1-azabicyclo [3.2.0] heptane-2-carboxylate);
14) Sodium (2S, 5R, 6R) -6-((R) -2-amino-2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2. 0] heptane-2-carboxylate (sodium (2S, 5R, 6R) -6-((R) -2-amino-2-phenylacetamido) -3,3-dimethyl-7-oxo-4-thia-1- azabicclo [3.2.0] heptane-2-carboxylate); and 15) potassium (2S, 5R, 6R) -3,3-dimethyl-7-oxo-6- (2-phenylacetamido) -4-thia- 1-azabicyclo [3.2.0] heptane-2-carboxylate (potassium (2S, 5R, 6R) -3,3-dim hyl-7-oxo-6- (2-phenylacetamido) -4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate).   A pharmaceutical composition for soft tissue hardening comprising the compound according to claim 1 or 2 as an active ingredient.   The pharmaceutical composition according to claim 3, wherein the soft tissue is at least one tissue selected from the group consisting of pancreas, liver, nerve, ligament, serosa, fascia, intervertebral disc and blood vessel.   4. The pharmaceutical composition according to claim 3, wherein the compound increases soft tissue hardness or tensile force.   A method of hardening soft tissue comprising the step of administering to a subject an effective amount of the compound of claim 1 or 2.   A pharmaceutical composition for preventing pancreatic leakage comprising the compound according to claim 1 or 2 as an active ingredient.   A pharmaceutical composition for soft tissue sclerosis comprising, as an active ingredient, a compound selected from the group consisting of a hydroxyquinoline compound, a derivative thereof, a pharmaceutically acceptable salt and a hydrate thereof. The pharmaceutical composition according to claim 8, wherein the compound is one or more selected from the group consisting of the following compounds:
16) 7-Chloro-4-hydroxy-3-quinolinecarboxylic acid (7-chloro-4-hydroxy-3-quinolinecarbo);
17) 5-Chloro-8-hydroxyquinoline;
18) 5-chloro-8-hydroxy-7-iodoquinoline;
19) 5,7-diiodo-8-hydroxyquinoline;
20) 4,8-dihydroxyquinoline-2-carboxylic acid (4,8-dihydroxyquinoline-2-carboxylic acid);
21) 4-hydroxy-2-methylquinoline;
22) 2-Hydroxy-4-methylquinoline;
23) 8-Hydroxy-5-nitroquinoline (8-hydroxy-5-nitroquinoline);
24) 4-Hydroxy-7-trifluoromethyl-3-quinolinecarboxylic acid (4-hydroxy-7-trifluoromethyl-3-quinolinecarboxylic acid);
25) 3-hydroxyisoquinoline;
26) 4-hydroxy-7-methoxyquinoline;
27) 4-hydroxyquinoline;
28) 6-hydroxyquinoline;
29) 2-hydroxyquinoline;
30) 7-hydroxyquinoline;
31) 8-hydroxyquinoline-7-carboxylic acid;
32) 8-hydroxy-5-quinoline sulphonic acid;
33) 8-hydroxyquinoline; and 34) 8-hydroxy-5-quinoline sulfonic acid hydrate.   The pharmaceutical composition according to claim 8, wherein the soft tissue is one or more tissues selected from the group consisting of pancreas, liver, nerve, ligament, serosa, fascia, intervertebral disc and blood vessel.   9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition increases soft tissue hardness or tensile force.   A method of curing soft tissue, comprising administering to a subject an effective amount of a compound selected from the group consisting of hydroxyquinoline (8-hydroxyquinoline) compounds, derivatives thereof, pharmaceutically acceptable salts and hydrates thereof. .   A pharmaceutical composition for preventing pancreatic leakage comprising, as an active ingredient, a compound selected from the group consisting of a hydroxyquinoline compound, a derivative thereof, a pharmaceutically acceptable salt and a hydrate thereof. A pharmaceutical composition for soft tissue sclerosis comprising a compound represented by any one of the following chemical formulas 2 to 9, a pharmaceutically acceptable salt or hydrate thereof as an active ingredient:
  The salt is sodium (6R, 7R) -3- (acetoxymethyl) -8-oxo-7- (2- (thiophen-2-yl) acetamide) -5-thia-1-azabicyclo [4.2.0. Oct-2-ene-2-carboxylate (sodium (6R, 7R) -3- (acetoxymethyl) -8-oxo-7- (2- (thiophen-2-yl) acetamido) -5-thia-1- The pharmaceutical composition according to claim 14, which is azabicclo [4.2.0] oct-2-ene-2-carboxylate).   15. The pharmaceutical composition according to claim 14, wherein the soft tissue is one or more tissues selected from the group consisting of pancreas, liver, nerve, ligament, serosa, fascia, intervertebral disc and blood vessel. A method of hardening soft tissue, comprising administering to a subject an effective amount of a compound represented by any one of the following chemical formulas 2 to 9, a pharmaceutically acceptable salt or hydrate thereof:
  The salt is sodium (6R, 7R) -3- (acetoxymethyl) -8-oxo-7- (2- (thiophen-2-yl) acetamide) -5-thia-1-azabicyclo [4.2.0. Oct-2-ene-2-carboxylate (sodium (6R, 7R) -3- (acetoxymethyl) -8-oxo-7- (2- (thiophen-2-yl) acetamido) -5-thia-1- The method of hardening a soft tissue according to claim 17, which is azabiccyclo [4.2.0] oct-2-ene-2-carboxylate). The compound represented by the following chemical formula 10 and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) (18-crown-6 (1,4,7,10,13,16) -Hexoxacyclooctadekane)) in an organic solvent;
Adding a compound represented by the following chemical formula 11 to the dissolved solution and stirring to synthesize the compound:
[Chemical formula 11]
R ₆ -Br
In Formula 10,
R is hydrogen or N (R ′) (R ″);
R ′ and R ″ are each independently hydrogen, a C _1-6 alkyl group or a C _1-6 alkenyl group,
In Formula 11,
R ₆ is hydrogen or a C _1-6 alkyl group;
The C _1-6 alkyl group of R ₆ is substituted or unsubstituted with R ₇ ;
R ₇ is selected from the group consisting of a C _1-6 alkenyl group, a C _3-7 cycloalkyl group, a cyano group, a C _1-6 alkyl group, a C _6-10 aryl group, —OR ₈ and —COOR ₉ ;
The aryl group of R ₇ is substituted or unsubstituted with halogen;
R ₈ is — (CH ₂ ) _n OR ₁₀ ;
n is an integer from 0 to 3;
R ₉ and R ₁₀ are each independently C _1-6 alkyl.   The compound represented by the chemical formula 11 includes 3-bromopropene, (bromomethyl) cyclohexane, 4-bromobutyronitrile, tert-butylbromopropionate. (Tert butyl brompropionate), 1-bromo-2-methylpropane, 1-fluorobenzyl bromide and 2- (2-ethoxyethoxy) ethyl bromide (2- ( 20. The method of claim 19, wherein the method is one or more selected from the group consisting of 2-ethyoxy) ethyl bromide). (A) measuring the hardness or tensile force of the pancreas of a mammal other than a human not treated with the compound;
(B) measuring the hardness or tensile force of the pancreas of a mammal other than a human treated with the candidate compound;
(C) the step of determining the compound as a pancreatic sclerosing substance when the hardness or tensile force of the pancreas measured in the step (b) is higher than the hardness or tensile force of the pancreas measured in the step (a) And a method for selecting a substance for pancreatic sclerosis.